The combined effects of ACNU and X-irradiation on cultured HeLaS3 cells were investigated. Pretreatment with either ACNU or X-ray induced a substantial reduction in shoulder width the D0 value of the dose-response curve for the other agent, given later was unchanged. ACNU did not inhibit the recovery of sublethal damage (SLD) induced by X-ray when this treatment preceded the split-dose experiment. Our results indicate that some cell damage induced by each agent is transmissible to the progeny of the surviving cells and that the interaction of ACNU and X-irradiation was lethal to the cells.

Twelve patients with recurrent breast cancer were treated with Peplomycin monotherapy. Peplomycin was given intermittently with a dose of 10 mg intramuscularly twice a week. As side effects of Peplomycin, fever elevation in 75% (9/12), malaise in 67%, nausea and vomiting in 42%, anorexia in 42%, pulmonary toxicity in 8%, and loss of hair in 8%, were observed. Out of 8 evaluable cases, CR was obtained in 1, PR in 1, NC in 3, and PD in 3 cases, respectively.

A combination chemotherapy "VEMA" consisting of vincristine (VCR), cyclophosphamide (Endoxan, EX), methotrexate (MTX) and nimustine (ACNU) has been carried out for the treatment of small cell bronchogenic carcinoma since September, 1978. "VEMA" regimen consists of VCR 1.3 mg/m2 iv push on day 1, EX 500 mg/m2 iv infusion on day 1 and 2, MTX 28 mg/m2 iv push on day 1, 2 and 3, and ACNU 67 mg/m2 iv push on day 3. This dose schedule was repeated every 3 to 4 weeks. The regimen was given to 14 patients and 12 patients were evaluable. In the 12 evaluable cases, 2 case of complete response (CR), 7 cases of partial response (PR) and 2 cases of effusion effective were obtained. Response rate of CR + PR was 90%. Response rate including CR, PR and effusion effective was 91.7%. The major clinical toxicity of "VEMA" therapy was bone marrow suppression. Other side effects were anorexia, nausea, vomiting, alopecia and stomatitis: etc; however, these side effects were not life threatening to terminate "VEMA" therapy. In conclusion, "VEMA" regimen is a new potent combination chemotherapy in the treatment of small cell bronchogenic carcinoma.

A concept of antitumor screening with rodent tumor models is discussed through the experience in the past 30 years, together with an introduction of a new system of antitumor screening in NCI, U.S.A., including a recently adopted mouse ovary tumor model. It is suggested that the more minute and elaborate studies of mode of action of the effect and toxicity of the antitumor drugs which are already clinically evaluated are useful to get new structures of compounds with antitumor activity into our minds. A new approach in studying drug resistance of tumor cells proposed by Ling is introduced that some of the acquired drug resistance is closely related to natural resistance of tumor cells which occurs by spontaneous mutation of the cells during proliferation.

In our laboratory, we have studied the mechanism of action of tumor-inhibitory antibiotics, including bleomycin, phleomycin, adriamycin, aclarubicin, neothramycin, macromomycin, auromomycin, chartreusin, pluramycin, neopluramycin, xanthomycin A, angustmycins A and C, blasticidin S and phenomycin. The recent advances are summarized. Screening of microorganism for new antitumor antibiotics based upon our studies on mechanism of action are currently ongoing. We are interested in drug-resistance of tumor cells, and have obtained drug-resistant sublines of murine lymphoblastoma L5178Y cells. We have found that glycoprotein synthesis and alkaline phosphodiesterase (APD) activity of the plasma membrane are higher in adriamycin (ADM)-, aclarubicin (ACR)- and bleomycin (BLM)-resistant cell sublines than in the parental cells. An inhibitor of APD has been isolated from a soil Streptomyces, and identified with 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone (COTC). COTC inhibits growth of the drug-resistant cells more significantly than the parental cells, and exhibits synergistic activity with ACR against ACR-resistant cells. COTC is a SH inhibitor. Although COTC is a multifunctional drug, the inhibition of DNA polymerase alpha and some mitotic process may be related to its lethal action. In the course of our screening, we have found that a strain of Sterptomyces hygroscopicus produces two substances: one inhibits thymidine and uridine uptake of human leukemic K562 cells, and the other stimulates it. The inhibiting substance has been identified with tubercidin, and the stimulating one has been found to be a novel pyrrolo [2,3-d] pyrimidine antibiotic, cadeguomycin. Cadeguomycin shows low acute toxicity in mice, enhances DTH reaction, and inhibits Ehrlich ascitic carcinoma in mice. The antibiotic exhibits synergistic effects with arabinosylcytosine against growth of K562 cells. Saframycin, discovered by Prof. Arai, Chiba University, is effective against Ehrlich ascitic carcinoma, P388 and L1210 leukemia, and B16 melanoma in mice. The target is DNA. Stubomycin, discovered by Dr. Umezawa, Kitasato Institute, is effective against Sarcoma 180, Ehrlich carcinoma, P388 leukemia, IMC carcinoma and Meth-A tumor in mice, and shows low acute toxicity. The target is plasma membrane.

Since 1970, we have carried out cancer chemotherapy and immunotherapy in cooperation with Japanese scientists, particularly Prof. H. Umezawa, who has generously supplied bleomycin, peplomycin, acalcinomycin A (ACM), THP-adriamycin (THP), neothramycin and bestatin. Malignant tumors curable by pharmacotherapy are polycythemia vera (CR 100%), acute lymphoid leukemia (ALL) (CR 80%), Burkitt tumor (CR 80 or 50%), Hodgkin disease (CR 80%), chorioepithelioma (CR 80%), testicular cancer (CR 80%), ovary cancer of children (CR 80%), Wilms renal cancer (CR 60%), rhabdomyosarcoma (CR 75%), osteosarcoma (CR 60%), Ewing tumor (CR 60%), brain tumor of children (CR greater than 50%), testicular embryonal cancer of children (CR greater than 50%), acute myeloid leukemia (AML) (CR 50%), non-Hodgkin lymphoma (NHL) (CR 50%), ovary cancer of adults (CR 40%), small cell lung cancer (CR 20%) and breast cancer. Our experimental and/or clinical experience with ACM, THP, methoxy-9-ellipticine lactate, navelbine, 4-demethyl-epipodophyllotoxin-beta-d-ethyledene glucoside, bestatin and interferon is presented. ACM is effective against AML, ALL, NHL, Burkitt tumor, breast cancer. We have comparatively investigated cardiac and dermal toxicity of 12 kinds of anthracycline antibiotics and mitoxantrone, using golden hamsters. Of the drugs examined, ACM, THP, AD-32 and AD-143 cause much less cardiomyopathy and alopecia than the other agents. The results have been confirmed by electron microscopic studies. Bestatin is an immunorestorator, which recovers immunological functions decreased in aged animals. We hope that cancer chemotherapy and immunotherapy will progress in future and contribute to cure of neoplasms. Japanese scientists have been making a great contribution in the field of cancer pharmacotherapy, and we are eager to cooperate with Japanese scientists in cancer treatment studies.

A phase II study of KW2083 [7-N-(p-Hydroxyphenyl)-Mitomycin C], a derivative of Mitomycin C, was carried out in 20 patients with carcinoma of the lung and in 19 patients with metastatic pulmonary tumor. KW2083 was administered by single intravenous injection at a dose of 20-30 mg/m2 weekly or a single 70 mg/m2 dose. Patients treated with a dose of 20-30 mg/m2 should be given at least 3 doses for eligibility. Of 17 evaluable patients with carcinoma of the lung (11 adenocarcinomas, 3 squamous cell carcinomas, 2 small cell carcinomas and 1 large cell carcinoma), two patients with adenocarcinoma showed a partial response (11.8%). Two patients who achieved PR had adenocarcinoma without prior therapy received KW2083 at a single dose of 70 mg/m2 Objective response rates were 18.2% for 11 patients with adenocarcinoma and 25% for 8 patients with adenocarcinoma treated with a single dose of 70 mg/m2 of 15 evaluable patients with metastatic pulmonary tumor, no patients showed any objective responses. The hematologic toxicities were thrombocytopenia (less than 5 X 10(4)/mm3, 41.6%) and leukocytopenia (less than 2000/mm3, 28.1%); it was observed in 19% of the patients, that thrombocytopenia continued for more than 6 weeks after stopping therapy. Gastrointestinal symptoms such as anorexia (81%), nausea (66%) and vomiting (16%) were severe in patients treated with a single dose of 70 mg/m2. Fever in 19%, alopecia in 13%, phlebitis in 9%, eruption in 6%, stomatitis in 6% and liver insufficiency in 13% were also observed.

In clinical practice, a number of tests are conducted to determine the immune reactivity of the patients. The principal cell in immunological surveillance against cancer has been thought to be the T cell. However, multiple immunological methods to evaluate the T cell function have failed to confirm a major role for the T cell in immunological surveillance. The role of other potential effector cells such as NK cells, K cells, macrophages and granulocytes needs more intensive investigation. In this report the effects of anticancer agents on immune effector cells were analyzed and the possibility about the development of a reliable monitoring procedure for determining a potent treatment protocol was discussed.

The effect of peplomycin by three different treatment schedules was studied in mice bearing Ehrlich Effeit of carcinoma. continuous i.p. infusion of peplomycin via an osmotic minipump was compared to those by intermittent injection and daily injection. Equivalent total doses of the drug were administered in all three schedules. Continuous infusion for 7 days produced marked inhibition of tumor growth, which was significantly better than intermittent injection or daily injection of the same total dose. The effect of bleomycin by continuous infusion was significantly better than that by intermittent injection, but was as equally effective was daily injection. The results indicate that the continuous infusion of peplomycin is a useful treatment method.

Sixty-three elderly patients with gastrointestinal cancer were treated with 5-fluorouracil (5-FU) or tegafur alone, and a combination of mitomycin C (MMC) and 5-FU. Judged by Koyama-Saito's criteria, the combination treatment was superior to single drug therapy. The response was somewhat correlated with survival in the combination regimen although it produced more gastrointestinal and myelotoxicities than the single drug. Our results suggest that the combination of MMC and 5-FU is useful in the treatment of gastrointestinal cancers in the elderly.

A new sensitivity test of anticancer agents was developed to measure the lethal effects of cancer cells by the incorporation of radioactive precursors. The thousand cancer cells were cultured in a microplate in the presence of anticancer agents. These cells were exposed to radioactive precursors. Two or three days later, the cancer cells were harvested on a glass fiber filter by a multiple automatic cell-harvester and the incorporation of precursors was counted by a liquid scintillation counter. In this study, the in vivo results of drug testing in animal model systems were compared with drug sensitivities. Mice inoculated Ehrlich ascites cells were treated with various kinds of anticancer drugs. The development of the cells was compatible with the result of the sensitivity test. The growths of Lauson and ME-180 cells derived from human cancers implanted subcutaneously to nude mice were also well correlated with this sensitivity test.

CAM is a derivative compound of mycophenolic acid produced by Penicillium brevicompactum, and is a new oral Purine antagonistic anticancer agent. The Phase I study was carried out cooperatively in ten hospitals. The results are as follows: The administration method was single administration and the starting dose was 200 mg/m2 (1n). The dose level was escalated according to varied Fibonacci formula. The number of total cases was thirty-one: three cases at 1n level, four at 2n, six at 3.3n, six at 7n and seven at 9n. Side effects were observed in five of thirteen cases over 7n dose levels, such as nausea, vomiting, anorexia and diarrhea. Leukopenia was developed in only one case at 7n dose level. Other side effects such as anemia, thrombocytopenia, and disturbances of liver function and renal function were not observed. It was estimated from above results that a dose limiting factor of CAM is nausea and vomiting. A subtoxic dose was 7n (1,400 mg/m2) and a maximum tolerated dose was 9n (1,800 mg/m2) which corresponded to 2,200-3,000 mg as a single administration.